Tumor necrosis factor α (TNFα) is involved in fumonisin-induced hepatotoxic effects in mice. The hepatic response to fumonisin B 1 (FB 1 ) was reduced in transgenic animals lacking either of the two TNFα receptors. In the present study, we hypothesized that the effect of a similar fumonisin treatment in animals lacking either TNFα or both TNFα receptors would be considerably less than their wild type (WT) counterparts. The FB 1 -induced increase in circulating liver enzymes was enhanced by deletion of TNFα or unchanged in mice lacking both TNFα receptors. These findings corresponded with the degree of toxicity as established by microscopic examination of liver. FB 1 induced the expression of TNFα in the liver of all strains, except the animals with a deleted TNFα gene. The FB 1 -mediated increases in liver sphingosine or sphinganine paralleled the hepatotoxic responses. It is apparent that the presence of TNFα is not necessary for FB 1 -induced hepatotoxicity in mice and a lack of the function of this cytokine may aggravate the hepatotoxic responses to fumonisins, perhaps by preventing repair mechanisms or by expression of other signaling molecules. These observations were in accordance with our previous finding where over-expression of TNFα also protected against FB 1 -mediated hepatotoxicity, and with the reported beneficial functions of low-level TNFα in tissue regeneration.